The goal of this proposal is to discover and design novel inhibitors of the proven anti-cancer target thymidylate synthase (TS) by combining phage display technology with structure-based drug development. Inhibitors will first be discovered by affinity-based selection from diverse combinatorial phage display libraries representing at least 1x10E7 potential inhibitors. Inhibitors discovered will then be characterized at atomic resolution to elucidate the molecular details of the TS-inhibitor interactions. From this structural information, succeeding generations of inhibitors will be designed in an iterative process in which new inhibitors are designed based on the structural information gained from the previous generation of inhibitors. The combination of diversity-based drug discovery with structure-based drug design will rapidly result in potent inhibitors of TS. In addition, a collaborative effort effort to discover novel inhibitors of E. coli thymidylate synthase using DOCK has recently been undertaken with Teri Klein of the Computer Graphics Laboratory. Analysis of protein-inhibitor interactions require the graphical capabilities of the CGL to analyze the three dimensional models of the TS-inhibitor complexes. The design and modeling of new inhibitors will require both graphical analyis of molecular models as well as computational analysis of the binding of newly designed inhibitors. The CGL possesses the hardware, software, and expert personnel to help me design novel inhibitors of TS.